Can we find ways to substitute frataxin?

The D’Autreaux laboratory is looking for new drugs to treat FA by screening chemical libraries with an enzymatic assay to find small molecules that can substitute for frataxin function in the cell. Iron-sulfur (Fe-S) clusters are small protein cofactors required for the catalytic activities of numerous enzymes whose biosynthesis is dependent on frataxin. This project aims to find small molecules substituting frataxin in order to restore Fe-S cluster biosynthesis in FA patients. Recent advances in the elucidation of frataxin’s biochemical function make this approach feasible today. The D’Autreaux laboratory has been studying the specific step involving frataxin during Fe-S cluster biosynthesis and, based on these data, developed an enzymatic assay that allows the screening chemical libraries to discover molecules replacing frataxin in Fe-S cluster biogenesis. A pilot study of 1,040 compounds from the French National Chemical Library was performed, validating the robustness of the assay. The investigators then performed a virtual screening, which is a computational technique to predict the ability of a molecule to replace frataxin. This virtual screening allowed them to pre-select a set of 420 molecules out of 80,000 with the highest probability of functioning as frataxin substitutes. The test of these 420 promising molecules led to the identification of 8 hits that are potential frataxin-substitute drug candidates. The aims of this project are to: i) test other molecules pre-selected by virtual screening, by sets of 5,000 molecules with the highest predicted ability to replace frataxin, ii) validate the hits of these screening assays in biochemical assays more specific for frataxin activity and iii) to perform virtual screening on another library containing 230 million molecules and test these molecules. The hits of the biochemical assays will then be tested in vivo in an FA fruit fly model to test the ability of these drugs to prevent, delay, or revert the phenotypes induced by frataxin deficiency. They also aim to better characterize the mode of action of the hits to improve the efficacy of the drugs. These drug candidates can then be tested in mouse models and ultimately in clinical trials.

Related Research Publications

PubMed | Mar 2022

Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich's Ataxia

Beata Monfort, Kristian Want, Sylvain Gervason, Benoit D'Autréaux